Polyglutamine (polyQ) expansion causes selective neurodegeneration in nine inherited neurological disorders despite the widespread expression of the disease proteins. The unique neuronal structure, which is characterized by numerous neuronal processes that interact with each other at their terminals, may confer the preferential vulnerability to expanded polyQ proteins. In Huntington disease mice that precisely and genetically mimic the expression of full-length mutant huntingtin (htt) in HD patients, degraded N- terminal fragments of htt preferentially form aggregates in striatal neurons that are most affected in Huntington's disease. Interestingly, these aggregates are predominantly present in the nuclei and neuronal processes and reside in presynaptic and postsynaptic terminals, consistent with the idea that the nucleus and nerve terminals are primary sites to be affected by the disease. This application will focus on mutant htt in axons and nerve terminals and aims to provide mechanistic insight into why mutant htt preferentially accumulates in nerve terminals and how it affects neuronal function. We hypothesize that the intracellular capacity of nerve terminals to clear misfolded polyQ proteins is more likely to decrease with age, leading to the accumulation of mutant htt in axons and their terminals. The increased accumulation of mutant htt then leads to abnormal protein interactions and neuronal dysfunction by affecting vesicular or protein trafficking. Since polyQ proteins are found to impair the proteasomal activity, it is also possible that mutant htt in nerve terminals affects the proteasome to mediate synaptic toxicity. We propose three Aims to test these hypotheses. In Aim-1, we will generate the proteasomal activity reporters that are specifically targeted to presynaptic and postsynaptic terminals for examining whether the activity of presynaptic and postsynaptic proteasome is lower than that in the cell body and is preferentially reduced by aging. In Aim-2, we will examine whether mutant htt affects proteasomal activity in nerve terminals of cultured neurons and in HD mouse brains. In Aim-3, we will investigate whether mutant htt affects actin-dependent vesicular secretion and neurotransmitter release, which are important for synaptic vesicular exocytosis and transmission. These studies will help understand the mechanism for the selective neurodegeneration in Huntington's disease and find the strategy to treat the early and specific neuropathology in Huntington's disease.